EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS, 1994, Vol. 19, No.2, pp. 107-117

Urinary excretion and metabolism of orally administeredmefenorex

S. RENDIC, M. SLAVICA and M. MEDIC-SARIC

Faculty of Pharmacy and Biochemistry, University ofZagreb, Zagreb, Croatia

Receivedfor publication: January 18, 1993

Keywords: Mefenorex, pharmacokinetics, metabolism, oral administration

SUMMARY

Metabolic pathways and the pharmacokinetic profile of mefenorex «±)N-(3-chloropropyl)-1-methyl-2-phenylethylamine), and itsmain metabolite amphetamine (l-methyl-2-phenylethylamine) have been studied in two healthy volunteers, after a single oral dose ofmefenorex (1.2 mglkg body weight for a male subject and 2.4 mglkg body weight for a female subject). Urinary concentrations weredetermined by gas chromatography (GC) and metabolite structure was identified by GCJMS following derivatization of urine extracts.The ratio of this metabolite to unchanged drug in urine samples, collected up to 5 h following administration, was essentially thesame after either of the administered doses.

The calculated KeI for mefenorex after the higher dose was in the range of 0.191-0.272 h-I, with a biological half life (tm) of3.98-2.55 h, depending on the method of calculation used. The elimination of amphetamine was much slower with a Kel rangingfrom 0.039-0.073 h- I and a tIn from 9.5-17.8 h. Depending on the dose administered, the rate constant of metabolite formation was0.129 and 0.685 h- I for low and high doses, respectively.

Urinary excretion of RondimenS amounted to 11.9% within 72 h after administration. Of this amount, 1.5% represented unchangeddrug and 10.4% represented metabolites. In addition to amphetamine 3 other metabolites were identified: p-hydroxy mefenorex,p-hydroxy amphetamine and p-hydroxy-m-methoxy mefenorex.

INTRODUCTION

Therapeutic application of the anorectic and stimulantdrug mefenorex is based on its metabolic conversionto its primary metabolite, amphetamine (1-3), and to aminor extent on its conversion to p-hydroxy amphe­tamine (1-3). Therefore, for therapeutically justified

Present address for Dr M. Slavica : Division of MedicinalChemistry and Pharmacognosy, College of Pharmacy, TheOhio State University, Columbus, OH 43210, USA.

Please send reprint requests to : Prof. dr. S. Rendic, Facultyof Pharmacy and Biochemistry University of Zagreb, A.

Kova~ica I, HR 41000 Zagreb, Croatia.

drug application it is important that the data on therate of metabolic conversion of the drug to the mainactive metabolite are available, as well as the data onthe pharmacokinetics of both the drug and the metabo­lite. In a number of drug testing programs, includingtesting of athletes, the urine sample is used as themost convenient (4). The identification of the metabo­lite(s) gives, in this case, additional evidence for thedrug having passed through the body. As has beenshown in the case of cocaine administration, if thedata on the ratios of the drug to metabolite are avail­able for different time intervals after drug administra­tion, estimates on the time of drug administrationcould also be made (5).

108 Eur. J. Drug Metab. Pharmacokinet., 1994, No.2

For mefenorex, approximately I% of a dose is ex­creted as unchanged drug within 72 h after oral ad­ministration (2,3). Previous studies of mefenorex me­tabolism in humans (2,3,6,7) have shown formation ofp-hydroxy derivatives II and IV (Scheme 1) in addi­tion to amphetamine. In die present study formation ofan additional metabolite in humans is reported,together with the pharmacokinetic parameters esti­mated from urinary excretion data for both the drugand the main active metabolite amphetamine.

Chemicals

The following reference compounds were used: me­fenorex hydrochloride (Homburg, FrankfurtlMain,Germany); dextroamphetamine sulfate (Smith, Klineand French, UK). All other chemicals were analyticalgrade.

Determination of partition coefficient(log P)

MATERIALS AND METHODS

Administration of the drug and samplecollection

Mefenorex (Rondimen@ dragee; 40 mg/dragee) wasgiven by p.o. route to a male subject at a single doseof 1.2 mg/kg body weight and to a female subject at asingle dose of 2.4 mglkg body weight. The drug wasadministered in the morning after the first meal.

Urine samples were collected before drug adminis­tration, and at random intervals within 72 h after drugadministration as indicated in Tables I and II. The col­lected samples were chilled and kept frozen until ana­lyzed.

The partition coefficient was determined by partition­ing mefenorex between octanol and water phases (8).The concentration in the water layer was determinedby UV-spectrophotometry, and that in the octanol wasobtained by difference. The partition coefficient wasdetermined as log P =Coctano)/Cwater (8).

The log P value for mefenorex was also calculatedaccording to the method of Rekker (9).

Extraction of urine

Extraction ofthe parent compound and unconjugatedmetabolites

A 5 ml urine sample, to which 0.5 ml 5 N KOH and 3g NaCI were added, was extracted with 2 ml of freshly

( II)

m/z 203 m/z 216/218---------~r------------

TFAI

'N~ClIt

TFAO :t

~t~ _2..3.? ~(I)

m/z 216/218m/z 91

TFAI

'N~CJItII

m/z 118/119:----------

m/z 118/119----------,I TFA, II

NHItII,I rn/z 140L. _

m/z 230------------,t, TFA, I

, 'NH

~~ :':

TFAO : m/z 140--------( Ill) (IV)

Scheme1 : Fragmentation pattern of mefenorex (I) and metabolites (II-IV).

S. Rendic et al., Excretion and metabolism ofmefenorex 109

distilled ether. The ether contained phenazine as an in­ternal standard. After extraction, the extract was cen­trifuged, dried over anhydrous sodium sulfate and sub­jected to GC analysis.

Extraction of conjugated metabolites and derivatiza­tion procedures

The urine sample (5 ml) was hydrolysed by heating at105·C for 30 min after addition of I ml of cone. HCIand 10 mg of cysteine. After cooling, the solution wasextracted with 5 ml of ether and the extract discarded.The aqueous layer was neutralized with 12 M NaOHand pH adjusted to 9.6 with a solid buffer (2 g, so­dium bicarbonate/potassium carbonate, 3:2). Thesample was extracted into etherlt-butano1 (5 ml, 9:1).After drying over anhydrous sodium sulfate, the or­ganic solvent was evaporated under vacuum at 3S·C.For GCIMS analysis, evaporated extracts were deri­vatized to their corresponding trifluoroacetamidesand/or trifluoroacetate esters using trifluoroacetic an­hydride (TFAA) and ethyl acetate as a solvent. Afterheating at 65·C for IS min, the solvent was removedin vacuo and the dry derivatized extract dissolved inanhydrous ethyl acetate for GClMS analysis. Alterna­tively the extracts were derivatized by the method ofselective derivatization (10,11) using N-methyl-N-tri-

methylsilyl trifluoroacetamide (MSTFA) and N-methylbistrifluoroacetamide (MBTFA) as derivatizing agents.

Gas chromatography (GC) and gas chromato­graphy/mass spectrometry (GC/MS) of urine extracts

GC analysis was performed on a Shimadzu GC 9Agas chromatograph equipped with a fused-silica capil­lary column (SE-54, 28 m x 0.25 mm 10, SUPELCO):the injector temperature was 180·C and a column tem­perature was programed at 60·C for 2 min, rising by20·C/min to 140"C and keeping the final temperaturefor S min. The carrier gas was helium at a flow rate of0.5 ml/min and the detector was NP RD.

GCIMS analysis was performed on a Kratos MS2S (Data General Nova 3 Data System) coupled withPerkin Elmer Sigma 3 gas chromatograph. The samecolumn as in GC analysis was used (1S m x 0.20 rom,10), with an injector port temperature of 28S·C (split­less injection) and a column temperature program of 3min at loo·C, rising by 16·C/min up to 285·C, andkeeping the final temperature for 10 min. The carriergas was helium at a flow rate of 1.2 ml/min. The col­umn was directly coupled to the mass spectrometer.The ion source temperature was 280·C and the ioniza­tion mode was electron impact at 70 eV.

Table I : Urinary excretion of mefenorex and its metaboliteamphetamine after oral administration of Rondimen® (male subject dose1.2 mg/kg body weight). Each value is the meanof at least 3 determinations,

Excretion interval UrinepH Amount excreted in intervals(p.g/ml) RatioAIM

(h)

o - 3.25

3.25 - 5.0

5.0 - 7.25

7.25 - 9.75

9.75-11.5

11.5 - 13.5

13.5 - 20.75

20.75 -23.75

23.75 -27.7

27.7 - 30.0

30.0 - 34.75

34.75 -37.25

37.25 -39.0

39.0 - 43.0

43.0 - 47.5

47.5 - 51.0

51.0 - 72.0

6.5

6.0

5.5

5.5

5.5

6.0

5.5

6.0

5.5

6.0

5.5

6.0

6.0

5.5

5.0

5.5

5.5

Mefenorex (M)

0.24

0.38

0.36

0.25

0.31

Amphetamine (A)

0.57

1.4

1.58

1.14

1.54

1.1

1.47

0.91

0.76

0.35

1.03

0.31

0.32

0.56

0.95

2.4

3.7

4.4

4.6

4.9

110 Eur. J. Drug Metab. Pharmacokinet., 1994, No.2

Table /I: Urinary excretion of mefenorex and its metabolite amphetamine after oral administration of Rondimen®(female subjectdose 2.4 mglkg body weight). Each value is the mean of at least 3 determinations.

Excretion interval Urine pH Amount excreted in intervals (~g/ml) Ratio AIM

(h) Mefenorex (M) Amphetamine (A)

0 - 3.25 5.5 4.0 10.19 2.5

3.25 - 5.33 5.5 4.7 19.77 4.2

5.33 - 9.5 5.5 3.1 30.33 9.8

9.5 -12.42 5.5 0.67 6.6 9.9

12.42- 14.75 5.5 0.25 6.98 27.9

14.75- 21.7 5.5 3.1

21.7 - 23.8 6.0 2.0

23.8 - 29.0 5.5 0.11 4.26 38.7

29.0 - 31.4 5.5 2.84

31.4 - 35.5 5.5 0.97

35.5 - 40.0 6.0 0.67

40.0 -49.2 5.5 1.19

49.2 -54.0 6.0 0.37

54.0 -57.0 7.5

57.0 -60.0 7.5

60.0 -64.6 5.5 0.59

64.6 -71.0 5.5 0.45

Quantitation ofthe compounds in urine samples

The extraction recovery for mefenorex from urinesamples of known concentration was 98 ± 2%.

Calibration curves were calculated by linear re­gression for concentrations from 0.1-1.0 flg/ml formefenorex and 0.1-6.0 flg/ml for amphetamine usingphenazine as an internal standard. The calibrationcurve for mefenorex in the range from 1.0-6.0 flglmlwas determined using non-linear regression. Calibra­tion curves were tested daily using at least 3 spikedblank urine samples of different concentrations.

Calculation ofpharmacokinetic parameters

Pharmacokinetic parameters were calculated from uri­nary excretion data according to standard proceduresdescribed by Wagner (12) and Gibaldi and Perrier(13). The results were fitted to a one compartmentopen model with first order absorption.

The elimination rate constant and the eliminationhalf life for both mefenorex and amphetamine werecalculated from: (a) the excretion rate; (b) the cumula­tive excretion curves, using the program KINMOD;and (c) the elimination curves using the programFARMOK.

Table /II: Cumulative amounts of urinary excreted mefenorex and its main metabolite amphetamine over period of 72 h followingoral administration of Rondimen®.

Dose Excretion ofmefen orex (M) Excretion ofamphetamine (A) Ratio

(mg) (mg)

0.25

1.21

(%)

0.63

1.5

(mg)

2.2

8.4

(%)

5.5

10.4

AIM

8.8

6.9

aMefenorex was detectable up to II h and amphetamine up to 47.5 h after administration of Rondimen® (1.2 mglkg body weight)"Mefenorex was detectable up to 29 h and amphetamine up to 54 h after administration of Rondimen® (2.4 mglkg body weight).

S. Rendic et al., Excretion and metabolism ofmefenorex 111

A B Table IV: Log P values determined experimentally andcalculatedby the method of Rekker (9).

...., Compound

Mefenorex

Methamphetamine

Amphetamine

Calculated

3.18

2.28*

1.98*

*Data from (14).

LogP

Experimental

3.47

2.16*

1.81*

wenzeenwa::

a::~owtio

I

RRT

Fig. 1 : (A) GC traces of the methanolic solutioncontainingmefenorex (6 ug/ml), amphetamine (25 ~glrnI) andphenazine (l0 ug/ml), (B) GC traces of the extractof urine samples spiked with the same amount ofthe compounds as in (A). Relative retention time(RRT): 1. amphetamine 0.283; 2. mefenorex 0.856;3. phenazine 1.000.

gradation is proportional to the increase of injectortemperature. In order to minimize the degradation, theinjector temperature was kept at 180·C. The GC tracesshowed good resolution of the parent compound frommetabolite enabling quantitation of both mefenorexand amphetamine in urine samples. The detection limitof this method was 0.1 ug/ml for both compounds.

Urinary excretion data for mefenorex and its mainactive metabolite amphetamine, following oral admin­istration of mefenorex are presented in Tables I-III.

Mefenorex and amphetamine were detectable inthe urine samples collected up to 11.5 h and 47.5 h,respectively, after oral administration of mefenorex(dose 1.2 mglkg body weight). The concentration ofamphetamine in all samples was higher in comparisonto mefenorex. Following administration of the higherdose (2.4 mglkg body weight), mefenorex was detect­able up to 29 h, and amphetamine up to 72 h afteradministration (Tables I-III). The ratio of metaboliteto unchanged drug concentrations (AIM) was "'2.5 inthe samples collected up to 3.25 h following oral ad-

mg

Fig. 2 : Cumulative elimination of amphetamine in urineafter oral administration of mefenorex (dose 1.2mg/kgbody weight).

The absorption rate constant for mefenorex at thehigher dose, and the rate constant for formation of am­phetamine were calculated from the simulated bloodlevel curves using the computer program FARMOK.

RESULTS AND DISCUSSION

Figure 1 shows the chromatograms of a methanolicsolution (A) and of the extract of a urine sample (B)containing known amounts of mefenorex, amphe­tamine and the internal standard phenazine. The peakwith relative retention time (0.639) arises as a conse­quence of thermal degradation of mefenorex. This de-

..I:

'E"i11e

<I(

3

2

10 20 30 40 50time (hI

112

A

Eur. J. Drug Metab. Pharmacokinet., 1994, No.2

B

mg

0,4

/"t-~---~+--'---'---~....V·......

........

mg

8

•c'E 6•;'&£ 4

10 20 30tlme(h)

10 30 50 70time (h)

Fig. 3 : Cumulative elimination of mefenorex (A) and amphetamine (B) in urine after oral administration of mefenorex (dose 2.4mg/kg body weight).

ministration of either dose. Also, the NM ratio in theurine samples collected between 3.25-5 h after oraladministration of the drug at either dose was similar=4. However, the NM ratio in the urine samples col­lected after the fifth hOUT following administration ofthe higher dose (2.4 mglkg body weight) rose to about30.

Delay in amphetamine excretion and its high urineconcentrations, following administration of the higherdose of mefenorex, may be explained by fast tissuedistribution of the more lipophilic parent compound,and its fast metabolism to amphetamine followingslow release from depot. The lipophilicity of mefeno­rex, expressed as log P =3.41 (determined experimen-

1.0

B

tally) or log P =3.18 (calculated), was compared withthe lipophilicity of amphetamine and methamphe­tamine (14) as shown in Table IV.

The overall NM ratio in the time period of samplecollection was 8.8 and 6.9 following administration oflower and higher dose, respectively (Table III).

While the major route of elimination for metham­phetamine (15,16) and ethylamphetarnine (11), undercontrolled acidic urinary conditions, is the excretion ofthe unchanged drug, only 1.5% of orally administeredmefenorex was excreted unchanged. Increased meta­bolism of mefenorex may be associated with the in­creased lipophilicity of the nitrogen substituent. As aconsequence, the excretion of unchanged drug was a

'"\,

\,

..... \-\ I-\

, ~

:"" ,-

~--...

~

I L

10 20t1me<hl

rTI

i~

3012 38 48 80

tlme(hl72

Fig. 4 Elimination curves of mefenorex (A) and amphetamine (B) constructed from the urinary excretion data after oraladministration of mefenorex (dose 2.4 mg/kg bodyweight) using the computer programFARMOK.

A

1.0

S. Rendic et al., Excretion and metabolism ofmefenorex

B

2

113

r

I" f\\ ...

I'-~........-

10 20tlmelh)

'ii'Zi:f•~ 1

30 48 60tlmechl

Pharmacokinetic parameters

minor route of elimination following both doses(Table III). Comparable results have been obtained formetabolism of n-butylamphetamine (18).

Fig. 5: Plasma concentration-time curves for mefenorex (A) and amphetamine (B) calculated by the computer program FARMOKfrom the urinary excretion data after oral administration of mefenorex (dose 2.4 mglkg body weight).

lated using different methods for each compound atboth doses (fable V): (a) from the cumulative excre­tion curves (Figs 2 and 3); (b) from the eliminationcurves (Fig. 4); and (c) from the plot of the elimina­tion rate of the drug (or metabolite) versus midpointtime (dAu/dt or dMuldt versus T). The use of the onecompartment-open model for calculations is justified

Pharmacokinetic parameters for unchanged drug and by suggested fast distribution of highly lipophilic me-amphetamine from urinary excretion data were calcu- fenorex. Similar assumptions regarding distribution

Table V : Pharmacokinetic parameters for mefenorex and metabolically derived amphetamine following single oral doses ofmefenorex, calculated from urinary excretion data.

Amphetamine dose

(mg/kg body weight)

Mefenorex dose

(mg/kg body weight)

1.2 2.4 1.2 2.4

1t/2 (h)

Ka (h-I )

Kc(h-I )

Au (mg)

0.039 1

0.0532

0.0403

17.81

13.12

17.33

0.1294

2.41

0.062

0.052

0.073

11.2

13.3

9.5

0.685

8.51

0.191

0.174

0.272

3.63

3.98

2.55

2.354

1.19

ICeI elimination rate constant; Ka absorption rate constant; Kr rate constant for formation of the metabolite (amphetamine);Au cumulative amount of uncharged drug excreted up to 72 h; tin elimination half life

1 calculated from the elimination curves; 2 calculated from the elimination rate; 3 calculated from the cumulative excretion curves;4 calculated from the simulated plasma concentration-time curves.

114 Eur. J. Drug Metab. Pharmacokinet.• 1994, No.2

100 209

m/z 216/218-jf-----

I

I TFAI , IN~Cl

THSO

OC"3 I

m/z 236I

- - - - ...J Ivl

m/z 209

90

80

70

73

60

50

236

40

30

179

20

141'16

10

91

0

50 100 150 200 250 300 350 400

Fig. 6 : Mass spectrum and fragmentation patterns of p-hydroxy-m-methoxy mefenorex extracted from urine after oral administrationof mefenorex (derivatized by 'selective derivatization' procedure).

and lipophilic properties were made for less lipophilicdrugs amphetamine and methamphetamine (19,20).

The absorption rate constant (Ka) for mefenorexwas 2.35 h-1 and the constant for formation of the me­tabolite (Kr) (amphetamine) was 0.685 h- l (Table V)and were calculated from computer simulated bloodlevel curves as shown in Figure 5A,B. The maximalblood concentration for mefenorex was achieved ap­proximately 1.5 h and for amphetamine at approxi­mately 4.5 h following drug administration. For calcu-

lations of blood level curves, it was assumed that atthe measured pH values of urine between 5.0-6.0(Tables I and II), the amount of the drug excreted inurine reflects the concentration of the drug in blood(Fig. 2) (13,21).

Pharmacokinetic parameters for mefenorex afteradministration of the lower dose could not be calcu­lated from urine excretion data since the values didnot achieve plateau in cumulative excretion.

We could not compare pharmacokinetic parameters

s. Rendic et al., Excretion and metabolism ofmefenorex 115

obtained from urinary excretion data for mefenorexwith pharmacokinetic parameters for other racemic N­alkylamphetamines. Extensive studies on urinary ex­cretion of the unchanged drug and metabolite amphe­tamine have been made after oral administration of the(+) and/or (-) isomers of N-alkylamphetamines(methyl-, ethyl-, n-propyl-, i-propyl, and n-butyl-)(15,17,18,20). However data on racemic N-alkylam­phetamines are insufficient for comparison with thoseobtained in the present study.

Identification of metabolites

Metabolites were identified by Ge/MS monitoring ofthe total ion current and extracted ion traces. Struc­tures and fragmentation patterns of metabolites identi­fied in urine samples after single oral administration ofmefenorex are presented in Scheme 1 and Figures 6and 7. In addition to amphetamine (III), 3 other meta­bolites were characterized (II, IV and V) (Scheme 1and Figs 6 and 7).

100 216

£:,'1

90

(V)

OCH]m/z 260

"rFAO

m/z 233 m/z 216/218.............. - - .. "lr' -

•• TFA., • I'N~Cl

,.... _- .. ------- ..

80

70

60

77

5056

140

40

260

30

20

91

10107

o

50 75 100 125 ISO 175 200 225 250

Fig. 7: Mass spectrum and fragmentation patterns of p-hydroxy-m-methoxy mefenorex extracted fromurineafter oral administrationof mefenorex (derivatized using TFAA).

116 Eur. J. Drug Metab. Pharmacokinet., 1994, No.2

~~CIMEPHENOREX (I)

0':(HO ~ HN~CI

p-Hydroxy-Mephenorex (II)

II ~

[~ ]HO ~ HN~CI

OH

3J

~HO ~ HN~CI

OCH3

p-Hydroxy-m-methoxy-Mephenorex (V)

Amphetamine (III)

~ 1

HOJY"

p-Hydroxy-Amphetamine (IV)

I MetabolicReactions I1. AromaticHydroxylation2. N·Dealkylation3. O-Methylatlon

Scheme 2 : Metabolism of mefenorex.

Metabolites hydroxylated in p-position (II, IV, andV) were identified after derivatization with trifluo­roacetic acid anhydride (TFAA) following hydrolysisof the urine sample. Amphetamine (1lI) and the parentcompound (I) were identified in the extracts of urinesamples without additional evaporation and derivatiza­tion. Compound V, p-hydroxy-m-methoxy mefenorex,was structurally characterized using derivatizationwith TFAA as well as using the method of 'selectivederivatization' (10,11). The latter method was used be­cause it produces more stable N-acetyl, O-trimethylsi­lyl-derivatives. By applying different derivatization re­agents to the same sample the proposed fragmentationpattern was confirmed. The mass spectra and fragmen-

tation patterns reported in Figures 6 and 7 indicate thatthe metabolic change in the aromatic ring resulted inp-hydroxy-m-methoxy mefenorex, Particularly indica­tive is the presence of the ions at m1z 425/27 and m1z410 corresponding to M+ and M-CH3 of compound V(Fig. 6).

Based on these identified metabolites, a metabolicpathway for orally administered mefenorex is pro­posed and presented in Scheme 2.

ACKNOWLEDGEMENTS

The authors thank all those who made a contribution to this

S. Rendic et al., Excretion and metabolism ofmefenorex 117

work, especially Dr Sanja Startevic (Institute for the Controlof Drugs, Zagreb) for kindly allowing us to use theShimadzu GC 9A, and the Kratos MS 25, without which thisstudy would not have been possible, and Dip!. Ing. Jasmina

Petrovic for her assistance in mass spectrometry (Institute forthe Control of Drugs, Zagreb). We would also like to thankProf. Dr Aleksandar Bezjak (Faculty of Pharmacy andBiochemistry, University of Zagreb, Zagreb) for providing

us with the KINMOD program, and Dr Franjo Plavsic(Medical School 'Rebro', University of Zagreb, Zagreb) formaking available to us the FARMOK program.

This work has been presented at the 11th CologneWorkshop on Dope Analysis, Cologne, Germany, March7-12, 1993.

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